How to Treat Localized Non-Small Cell Lung cancer – Treatment Algorithm with Dr. Sanjay Popat

[MUSIC] We are at the oncology brothers. >> Hello and welcome back to another episode of the oncology brothers podcast. I'm Rahul Gossane, joined as always by my brother and co-host, Rohit Gossane. In our ongoing series of treatment algorithms, today we're focusing on early stage non-smalsa lung cancer, resectable or unresectable, but the treatment here is with curative intent. Let's talk through the role of NGS here. Who should get post-op I/O? Can we extrapolate maintenance data to other actionable mutations? There's a lot to unpack and we're excited to have a leading thoracic medical oncologist, Dr. Sanjay Popet from London, England. Sanjay, thank you so much for joining us. >> Absolutely. Pleasure to have you. >> Sanjay, welcome. Let's dive into the world of curative intent non-smalsa lung cancer. Where the first and foremost important step is proper staging. That is with lymph node evaluation and also assessing that brain tumor burden if there is any on MRI brain. Then talking about the neo-adjuvant treatment options. But before we even do that, upfront NGS is rather essential, especially when we have therapies for each year for positive disease as well as alt mutated disease because in those cases, I/O should be rather omitted. Sanjay, could you please walk us through your approach with regards to NGS testing? What's your workflow like? >> Yeah. The world has moved on since the era of targeted therapeutic immunotherapy and pre and perioperative therapy. We've got to make sure we do a proper CT scan. So the surgeon can actually identify where the primary is in relation to the fishes, the major vessels, the high lerm. So we can really get a good sense of operability. We need to do an FG-FG PET scan so we can better understand the motivation of metastatic disease or not. Those two are critical. We need to have MR-Brate with gadolinium enhancement. So we need to know whether the patient has CNS metastasis or not. We need to have up to date formal lung function with gastronomphyrs, so we need to better establish what the post-operative lung function is going to be like and whether the surgery is really on the cards for these patients. These patients need a pre-optid diagnosis. And if there's any hint that we've got metastinal nodes involved, they must have a pre-operative e-bust to stage the metastinal. What you want to be is knowing all this information up front. So you know what type of lung cancer it is. So the surgeon going in knows exactly which nodes are involved before the surgery. So they can plan the type of surgery that they're going to do. So e-bust is really important. If we don't think there are any nodes involved, it's completely cold in the metastinal, or it's not a large tumor, it's a peripheral tumor. We can get away really just with a sampling of the primary tumor. Then when the pathologist has told you that this is non-sforceful lung cancer, of course we need to know what we're dealing with, whether it's an adenine or a squame. It's really mission critical that we have NGS, right? Because your NGS is going to tell you whether that patient goes straight to surgery, whether we do pre-operative treatment, what the treatment options are. And within the NGS, I would say like to understand the PDO1 status, because that gives me a handle, or if we're thinking about immunotherapy, how likely am I going to get a pathocion in that patient? Sanjit, thanks for starting us. So three things in mind, we need staging, we need to know what type of histology and NGS is critical. So with all that, let's talk about the data in hand, particularly starting off with no actionable mutations up front. Here for neo-adjuvant chemo-munotherapy, we have checkmate 816, which is three cycles of chemo with novolumab upfront for that resectable disease. Here we have updated overall survival benefit at five-year mark, which is OS of 65.4% versus 55% with chemotherapy alone, and has a ratio of 0.72. This has been the standard of care since the approval of this regimen. In this space, we have multiple options, pretty much one for each immunotherapy, be a novolumab, dervalumab, or Pembrolezmab, and all with perioptreatment, and then continued post-op immunotherapy as well. But given improved OS with just three cycles of chemo and novolumab, Sanjit, in your clinic, who gets that post-op IO? This is really the hot question that we have in our clinic state of name, right? And I don't think we really know the answer to this question. You know, there is one trial ongoing in Europe, which is actually looking at this. I think you guys in the US also have a similar study. The Adopt study is a non-US global study, randomizing to just preoperative or periopt in non-pathy observations. It'll help us understand that. But in the interim, you and I have to make decisions in the clinic, right? So what we do, so these are where I think the decision making between the individual physician and the patient is paramount, because you can argue things both ways, right? So we see some patients who've sailed through the chemo IO, they've had a pathosy, you know, quite comfortable. I think many of those patients with a pathosy, are that, you know, maybe more immunotherapy is not necessarily going to be that beneficial for them. You've seen very nice curves from the 816 study in patients with pathosy, are with almost flat Lyme, EFS, for no relapses if you've had a pathosy, but in some of the perioperative studies, we have seen a few events, and the most recent ELCC meeting in the QNOT 6.1 meeting of the outcomes of patients with pathosy, a small proportion of patients did have progression events. Now, was that going to happen anyway, or, you know, has the immunotherapy pushed that out? We don't know, because we don't have a randomized comparison, right? So I think what we know is that if you have a pathosy, your outcomes are going to be really, really good. Do you need immunotherapy afterwards? I think that's arguable. A lot of people would say, you know, if we've got co-pays to think about, if the patient got beat up with it, if we're running into problems with toxicity, I don't really want to push that. So these are the things that are going through my mind when I see a pathosy, am I comfortable about not giving an IO in a pathosy? Yeah, relatively comfortable, but I also know that I've got a trust that that pathosy is a real pathosy. Have I really known that they've, you know, resected all the nose? Has there been a good nodal dissection? Am I concerned about anything about the residual that's there? If I am, then I might be keen on to do more. There are many that argue that if you don't have a pathosy, right, that you have a major pathosy called response, or even very little response, right? You know, you've got 90% residual viable tumor. Then what's the point in giving more immunotherapy? Because three cycles hasn't gone on top of it, then why am I giving more? Right? So these are the uncertainties that we have. These are the things that I think about with a patient. You know, once they're journeyed being like two surgery, was it plain sailing? Was it difficult? Are they having impacts with the immunotherapy, both financial travel, other issues that we need to think about? You know, having a discussion with the patient is really important. Some people come to me and say, "Hang on, what do you mean?" "I've got an option of immunotherapy, you're not giving it to me?" For those patients, sure, you know, we would go ahead. Right. For other patients, they would say, "What do you mean you want more treatment?" Right, that's crazy. Right? So for those patients, I would say, "Well, that's okay. You know, these are the data, these are the uncertainties." So a lot to think about in this setting. Thanks so much for summarizing that, Sanjay. With what you stated at the end of the day, is patient shared decision-making is part of the key aspect here. In addition to that, we'll see how the CTDNA really plays out. Sanjay, what we have covered is rather periop or neo-adjuvant. But how about if that patient has undergone surgery a front? And now we are deciding on that treatment option, which is platinum-based adjuvant chemotherapy. But what is that patient that you will add immunotherapy? Will PDL1 help you in decision-making there? Yeah, I think it does, right? You know, the PDL1 score in the metastatic setting is the key driver of benefit. And, you know, we have two trials that have really contributed to the decision-making around the adjuvant setting, right? We've got the Empower 1/0 trial and we've got the pearls from WOST. You've got a label that would 1% and above. All the actions really in the TPS 50% and above. Yes. And really the OS benefit, right? I mean, if S is important, but OS is really important, right? Given the toxicity, both to the patients, the financial toxicity, to the system, and also the patients, right? That this causes, we're going to think about all of these things, right? And so for me, you know, Empower 1/0 has an OS benefit in the 50% group. So the 50% group are definitely in group that I would prioritize. Now, pearls is the adjuvant study, and that has caused a bit of a mess with the whole thing. We were expecting to do really well the TPS, and all the 50% above didn't have a benefit. That may be because the control on overperformed, difficult to know, but in the whole ITT population, overall, there was a meaningful benefit. We do have a label for Pembro in negatives, 1 to 49 and 50%. And I think we've got some uncertainty when it comes to the Pembro decision making, as to what the benefit is. So certainly, in my practice, I prioritized the more than 50% whether given Pembro or a T-Zo, I think is an individual decision. the 1-49s on the not sure about. I think there are probably some benefit for EFS, not sure about OS, so that's the discussion to have. In the PIL1 negative patients, I'm not convinced that we have a strong benefit at all. So those patients are very comfortable in not having an immunotherapy component in the adjuvant setting, but this goes back to individual shared decision making right because of the absence of data that have very much so and couldn't agree more, but that was all for if you did not have actionable mutation. Now, if one has actionable mutation, that is we have two approved agents here for our positive disease, we have electoneb, for each EFR positive, we have Aussie Mertnib. Diving into the Aussie Mertnib story, this was approved based on Adora trial where adjuvant Aussie Mertnib after chemotherapy is to continue on for three years time where we've seen oral survivor that is for five years 88% with Aussie Mertnib versus 78% with placebo for stage 1b23a and electoneb, which is based off of Alina trial. Alina trial showed that electoneb is for two years in adjuvant setting for out positive disease where we have DFS benefit, that is 94% versus 63% with chemo with hazard ratio of 0.24, the oral survival is immature here, but interesting part was that the comparator arm was active chemo. So the big question here, Sanjay is who should get chemo in addition to these targeted therapies, any patient population that you would omit chemo and just go for targeted therapy here? This is another great area of controversy where we have very little data to go on. So, you know, my view is we go back to first principles, right? When the first principle is we know that adjuvant chemotherapy increases the cure rate, which is the right, it increases the overall survival rate at year five, increases the PFS rate or EFS rate at year five as well, right? So we know that adjuvant chemotherapy is bringing something to the table. Then there's the other issue about what is the magnitude of that benefit? Have you got other agents that you can give and how long are you giving those other agents for? Because that's another big unknown currently have. And in the EGFR fields, I'd already did allow chemotherapy if that was felt in the interest of the patient and a reasonable proportion of patients did get adjuvant chemotherapy. The patients that didn't get adjuvant chemotherapy tended to be the one piece where there's always been a questionable benefit for adjuvant chemotherapy. So in my practice, I'm relaxed about chemotherapy in that group of patients because the survival benefit is questionable. We know that there is a strong benefit from adjuvant osseumotinib. I'm quite relaxed about putting them on the osseumotinib straight away. However, if they're fit and I think we've got an opportunity to get chemo in without compromising care, without resulting in morbidity or hot emergency hospitalization or other complications, then yeah, I'd be having a chat with them about a chemotherapy. For the stage 3, people argue at both ways. We've got one group of physicians which will say, hang on, this is a high-miss disease. We've got to be able to do the best job first, which is chemotherapy and the other group of physicians saying, well, actually, yes, high-miss disease, which is why we're going to do something that's going to cure them, right? And we know that chemo cures my personal view is for stage 3s. I tend to give them chemotherapy upfront with a view to then keeping osseumotinib afterwards. We don't really have data to say we should be giving them together at the moment. Chemo or osseumotinib, which is what we do for metastatic disease. We don't have that data at the moment for the adjuvant setting, which is why I'm not doing that in the adjuvant setting. Maybe that's where we'll go in the next few years. It becomes even more controversial in the outspace because in the outspace, the trial did not randomise against chemo, right? It was just basically lectinib or not, right? So we have no data. My views on it are quite similar. To be honest with you, we are curing patients with chemotherapy. There's always a question about whether we're curing patients with TKDIs, right? Because when you look at the longer follow-up of EGFR, you stop the treatment at year three, pimping, pimping, pimping. We now have relapse events kicking off, right? So you want to think about that. And I generally would like to give my patients chemotherapy upfront, get that out of the system, and then we will go in for the TKDIs. Then there's a discussion about how long do you carry on the TKDIs for? Absolutely. You know, my practice is very similar for that stage two, B, three A healthy patient, recacted, Alc or EGFR positive, Aline into chemo, and then start with that targeted option because there is that OS benefit that we know with chemotherapy. Sanjay, are there any particular mutations where you would extrapolate this data like adora and Aline, and give targeted agents for resectable disease for other mutations? Part two, we have Zonger Tene from your work. What about met Exxon skipping mutation? There's press release for ret mutation as self-percate Teneb is showing EFS in this setting's your thoughts here. Yeah, so I mean, I think for red, you know, we've got a data set which will be shortly presented, showing a massive EFS advantage. And you know, when we get that data, I'm sure that's going to be standard care pretty much overnight, right, if you can access the drug. So that I think to me is pretty, pretty straightforward, you know, I like to see the data before I jump in with my, with my legs first, right? That's the general principle I have, because I need to understand risks and benefits, right? You can't have a patient. Absolutely. Yeah. So otherwise it's just prayer, really. So, you know, I think for red, we're definitely going there. We've got trials that are recruiting, and they're difficult to recruit to because of the rarity of the population, right? I am not convinced that Frizzo is the best prompt to use in that setting. We probably want to be using the next generation roles inhibitor. We have trials on going of tantatrectinid. You know, we'll have to see how that pans out. It would make sense if those were positive, given what we've seen in this never smoking population of patients out and EGFR, ret data to be presented, rosdata, still recruiting, but I think we all pretty much know where we're going with that disease. The other gene has become more problematic, right? So, you know, metaliototherapy, cat-maths, nip, tepotent is not a walk in the park, right? This is tough. Kind of is inhibitor. Sorry. We see a lot of adverse events. We see a lot of peripheral edema. We see a lot of elevation or serum creatinine. Patients find it tough love. So, the problem I've got with met is what is the magnitude of difference benefit that I'm getting for a met inhibitor, which I don't know how long to use for, by the way, two years or three years. This isn't unknown. So, I'm not rushing into mettherapy in my practice at this point, but I can understand why folk might want to rush into it, but it's tough to work. The Zorganism study will be recruiting, so we will get some data on that. Do we really know? So, you know, one of the problems that we have is we think we know the answer to these questions, but actually when we see the data we don't, and it is a good example, right? Adjuvant Chrysostomine for outpostal disease, say, I don't think it's going to be easy, right? No problem. Well, actually, it's a negative study. So, what we think doesn't necessarily translate to what we know in the end. And I think that's a say, lesson for a lot of holding fire, recruit to the study, and then we're going to get a lot, so then we can move forward. Well, thanks for covering that, Sanjay. With regards to similar story here, where you have outpostal disease and EGFR positive disease, you are omitting immunotherapy. Of course, there's no advantage there, but how about for these other commutations that we were just talking about, if those mutations are present, are you omitting immunotherapy in that setting? Yeah, I think it depends on the nature of the mutation, right? So, you're classical IO insensitive mutation, like a red fusion or a rose fusion. I don't really see a role for immunotherapy in that setting. We don't have good data to justify that, but we're making extrapolations from other datasets. We know in the metastatic setting that these crumbs do next to nothing, but on the therapy. So, why should that be any different in the case of the set? We've seen subset data for me, GFR showing that, we've seen retrospective data showing that. So, to me, I don't really think we need to try to prove that. I think these patients are better off without even the therapy. When it comes to the possible immune sensitive genotypes, like B-Raff, like K-RASG12C, like met 14, it's another ball going, right? So for G12C, we know that these genotypes are probably sensitive to checkpointing. It does, they must get a checkpoint in emitter in my view. And for B-Raff and met 14, I still think these genotypes can be effectively treated with checkpoint inhibitor. So, I do offer them to Valema in the inoperable post-chula radiation analysis. Well, we have covered quite a bit from early aspect of resectable setting. Now, moving along into unreceptible space. If there are no actionable mutations present, what we have been utilizing is chemoradiation followed by Duvalemab. This is based off pacific trial. What we have here is the five-year oral survival data that is 43% with Duvalemab, or 33% with placebo, with hazard ratio about 0.72. As a result, this in fact is the standard of cure. But in Europe, Sanjay, this is based on PDL1 score. As a result, if PDL1 status is rather negative, would you hold off under Valemab? That's right. So, this is based on the email you're European Medical Association authority who did ask the sponsor for a post-hoc unbound analysis by PDL1 negative or positive because the medical trial was designed back in those days, developed and developed on a sort of 25% threshold. So they actually tried to stratify by 25% positive or negative above or below, not the 1% so they went back and looked at that and in the post-hoc analysis there was no PFS benefit or OS benefit. Now you can argue that it's an uns stratified group of patients, there are many other covariates that might be going on. And of course the other bigger issue is that that's a diagnostic PDL1 status and we know that chemo-radiation can change the PDL1 expression of humans so it's not a contemporaneous PDL1 status. So many have argued that that decision is wrong. However that is the decision that the European Medical Agency has made and that has driven a lot of the reimbursement decisions and in Europe, PDL1 negative patients generally don't get treated with government. What you may not have seen actually is an Asian study called Pacific 5. Now that presented at this Malaysian a couple years ago and that's a big randomized phase 3 trial of development exactly in the same setting. Instead of just taking con-correct chemo-radiation it took sequential and con-correct chemo-radiation patients and randomized them to develop a life not just the one year or no development. Very similar to Pacific 1 that we had. This study was stratified at PDL1 status and actually in that study PDL1 negatives have no benefit from the FS. We've seen similar trends around approval here in the US versus in the Europe where FDA here ends up being more liberal. Just before we close after con-correct chemo-radiation we also have Olsumrtenib based off Laura Trial if you have EDGF-R mutated disease. Phenomenal data but here treatment is lifelong. That can be daunting. Sanjay are you extrapolating this after con-correct chemo-radiation for out-positive disease for other mutations like retouched in adjuvant settings? Yeah I think we can make this very strong argument to do so. We actually had a couple of trials planned in the post-chema-radiation space, one with electinib and one with brigatinib and these trials for many feasibility reasons will not recruit further. So I don't think we're going to get randomized data in this setting are retrospective chart review type of database data clearly demonstrates a benefit in the out space. I think it's very reasonable to extrapolate the data for the out space that we've seen from the Laura trial in the EDGF-R space. We don't have data in the raw space and we don't have data in the red space but I think it's very reasonable to make those same extrapolations. Again for the med space not rushing into med targeted therapy because it's a tough class of drugs to give and very similar for the B-Raff space. We don't remember when we look at the control on from Laura, many patients relapse within two months. So the other option is to keep an eye on your patients and if they do relapse you just start at the point of PD because that's often what we see here. So I'm hoping CTDNA will help us somewhere here as well but I know the lifelong is not easy but argument on the other side is that this is essentially metastatic disease and if one is able to tolerate these therapies without any major side effects yes there is financial talk city one has to tie in but still again the patient shared decision making still becomes a key here. Wow we ended up packing quite a bit Sanjay. Thank you so much for sharing your thoughts around the treatment paradigm for curative intent non-small cell lung cancer for you tuning in. Stick around for a quick recap from today's discussion. Today with Dr Sanjay Popeye we walked through the treatment algorithm of non-small cell lung cancer with curative intent. Our front NGS testing on tissue is essential before we commit to neo-HVinqimo immunotherapy in that resectable disease. Patients with actionable mutations like EGFR or ALC should not receive that chemo IO. If chemo IO is the right option then we have strong data for checkmate 816 which is three cycles of chemo nivolumab. Here at five years we're seeing improved overall survival which is 65% with this approach versus 55% with chemo alone. We also touched on who often gets that additional IO in post-op settings. The data is all over the place. Rohat what else do you want to highlight here? Rohal for resectable disease we also touched on Aussie Martinib data from Adora trial and Electinib from Alina trial should all with EGFR or ALC positive disease get chemotherapy can be extrapolate this data to other actionable mutations. We have already seen positive press release around red mutation and then to close off we touched on post-chemo radiation in un resectable disease where we have mature data from the pacific trial and also Aussie Martinib approval based off of Laura study. Here again we brought up if we can extrapolate targeted options after chemo radiation if actual mutations are present. Thank you for tuning in. Be sure to check out our other episodes in the treatment algorithm series. We look forward to seeing you soon at ASCO2026 in person. We are the oncology brothers.